DOCSLIB.ORG

TRPC Channels in Proteinuric Kidney Diseases

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
TRPC Channels in Proteinuric Kidney Diseases cells Review TRPC Channels in Proteinuric Kidney Diseases Gentzon Hall, Liming Wang and Robert F. Spurney * Division of Nephrology, Department of Medicine, Duke University; Durham, NC 27710, USA; [email protected] (G.H.); [email protected] (L.W.) * Correspondence: [email protected]; Tel.: +1-919-684-9729 Received: 18 November 2019; Accepted: 19 December 2019; Published: 23 December 2019 Abstract: Over a decade ago, mutations in the gene encoding TRPC6 (transient receptor potential cation channel, subfamily C, member 6) were linked to development of familial forms of nephrosis. Since this discovery, TRPC6 has been implicated in the pathophysiology of non-genetic forms of kidney disease including focal segmental glomerulosclerosis (FSGS), diabetic nephropathy, immune-mediated kidney diseases, and renal fibrosis. On the basis of these findings, TRPC6 has become an important target for the development of therapeutic agents to treat diverse kidney diseases. Although TRPC6 has been a major focus for drug discovery, more recent studies suggest that other TRPC family members play a role in the pathogenesis of glomerular disease processes and chronic kidney disease (CKD). This review highlights the data implicating TRPC6 and other TRPC family members in both genetic and non-genetic forms of kidney disease, focusing on TRPC3, TRPC5, and TRPC6 in a cell type (glomerular podocytes) that plays a key role in proteinuric kidney diseases. Keywords: transient receptor potential cation channel; transient receptor potential canonical channel; TRPC channel; focal segmental glomerulosclerosis; diabetic kidney disease; diabetic nephropathy; chronic kidney disease; TRPC6; TRPC5; TRPC3 1. The Burden of Chronic Kidney Disease (CKD) CKD is a public health problem that affects more than 20 million Americans in the United States [1]. The disease is caused by a diverse group of primary, secondary, and genetic disorders that impair the ability of the kidney to remove waste, regulate intravascular volume, reclaim essential nutrients, and stimulate erythropoiesis [2]. As the disease progresses, these essential functions become increasingly impaired, eventually leading to end-stage kidney disease (ESKD). Of the 20 ≈ million Americans with CKD, almost 600,000 have irreversible kidney failure and require either renal transplantation or dialysis to sustain life [3]. The expense of providing ESKD care to this patient population costs 50 billion dollars per year in the United States [3]. Moreover, morbidity and mortality ≈ are markedly increased in CKD patients with lesser degrees of renal impairment, which is largely caused by an increased risk of cardiovascular events as renal function declines [1,4]. Although current treatments for CKD may slow disease progression, many patients progress to more advanced stages of CKD, and ESKD, despite available therapies [2]. As a result, there is a significant interest in developing new treatment approaches. 2. The Glomerular Podocyte Plays a Key Role in Proteinuric Kidney Diseases Podocytes are highly differentiated, postmitotic cells that play a critical role in maintaining the integrity of the glomerular filtration barrier [5]. As shown in Figure1A,B, their interdigitating foot processes (FPs) cover the exterior surface of the glomerular basement membrane (GBM), and form a specialized intercellular junction between adjacent FPs known as the slit diaphragm (SD) [6]. The SD is a sieve-like, size-selective filtration barrier, which prevents loss of cells and macromolecules into the Cells 2020, 9, 44; doi:10.3390/cells9010044 www.mdpi.com/journal/cells Cells 2020, 9, 44 2 of 24 glomerular ultrafiltrate [7,8]. It is composed of proteins commonly found in tight and adherens junctions such asCells P-cadherin, 2019, 8, x zonula occludens-1 (ZO-1), and catenin family members, as well as proteins2 of 24 predominantly expressed in podocytes including nephrin, neph1, and podocin [7,8]. Both nephrin and neph1junctions are members such as P- ofcadherin, the immunoglobulin zonula occludens (Ig)-1 (ZO superfamily-1), and catenin [7]. Theirfamily extracellular members, as domainswell as containproteins multiple predominantly IgG-like motifs, expressed which in can podocytes aggregate including and form nephrin, zipper-like neph1, structuresand podocin that [7,8 surround]. Both the glomerularnephrin capillaries,and neph1 are creating members a sieve-like of the immunoglobulin filtration barrier. (Ig) Both superfamily nephrin [7] and. Their neph1 extracellular also have a domains contain multiple IgG-like motifs, which can aggregate and form zipper-like structures that single transmembrane domain and a short intracellular carboxy-terminus, which serves as a scaffold surround the glomerular capillaries, creating a sieve-like filtration barrier. Both nephrin and neph1 for assembling signaling complexes with other podocyte proteins such as CD2AP (CD2-associated also have a single transmembrane domain and a short intracellular carboxy-terminus, which serves protein)as and a scaffold podocin for assembling [8,9]. The signaling carboxy-terminus complexes ofwith nephrin other podocyte has conserved proteins such tyrosine as CD2AP residues (CD2 that- can be phosphorylatedassociated protein) by and Src podocin family kinases[8,9]. The [7 ,10carboxy–13].- Phosphorylatedterminus of nephrin nephrin has conserved recruits additionaltyrosine signalingresidues molecules that can to thebe phosphorylated scaffolding complex by Src family that, in kinases turn, influence[7,10–13]. Phosphorylated multiple downstream nephrin recruits signaling pathwaysadditional and modulate signaling cytoskeletal molecules reorganization,to the scaffolding cellular complex survival, that, membranein turn, influence trafficking, multiple cellular adhesion,downstream and mechano-signaling signaling pathways [7,10 ,14and,15 ].modulate cytoskeletal reorganization, cellular survival, membrane trafficking, cellular adhesion, and mechano-signaling [7,10,14,15]. Figure 1. Glomerular ultrastructure and TRPC family members. (A) An electron micrograph of Figure 1. Glomerular ultrastructure and TRPC family members. (A) An electron micrograph of glomerular ultrastructure is presented. The podocyte cell body is located in the urinary space on glomerular ultrastructure is presented. The podocyte cell body is located in the urinary space on the the outerouter surface surface of theof the glomerular glomerular basement basement membrane (GBM). (GBM). Primary Primary processes processes extend extend from fromthe cell the cell bodybody and and branch branch into into interdigitating interdigitating foot foot processes processes (FPs) (FPs) that that cover cover the external the external surface surface to the GBM to the GBM (black(black arrow arrow heads)heads) to to form form filtration filtration slits slits and and the specialized the specialized intercellular intercellular junction junction termed the termed slit the slit diaphragmdiaphragm (SD). (SD). The The glomerular glomerular filter filter is composed is composed of the ofpodocyte the podocyte FPs with FPs the withintervening the intervening SDs, the SDs, theGBM GBM (black (black arrow arrow heads) heads),, and anda fenestrated a fenestrated endothelium endothelium (white arrowheads) (white arrowheads) that lines the that capillary lines the capillaryloops. loops. (B ()B )This This high high power power view view shows shows the the three three layers layers of of the the glomerular glomerular filter filter including including the the fenestratedfenestrated endothelium endothelium (white (white arrowheads), arrowheads), GBM GBM (black (black arrowheads), arrowheads), andand the FPs FPs (white (white arrows) arrows) with thewith interposed the interposed filtration filtration slits (black slits (black arrows). arrows An). An asterisk asterisk indicates indicates a a primary primary process (also (also termed termed a major process). (C) The phylogenetic tree of TRP family members is shown in panel C. The a major process). (C) The phylogenetic tree of TRP family members is shown in panel C. The vertebrate vertebrate TRPC family has seven members, which are divided into four subgroups: TRPC1, TRPC2, TRPC family has seven members, which are divided into four subgroups: TRPC1, TRPC2, TRPC4/5, TRPC4/5, and TRPC3/6/7. The figure shows the relationship between TRPC family members and and TRPC3other/6 /members7. The figure of the shows TRP family. the relationship In humans, betweenTRPC2 is TRPCa pseudogene family (see members text). and other members of the TRP family. In humans, TRPC2 is a pseudogene (see text). Cells 2020, 9, 44 3 of 24 In addition to their role in forming a size selective filtration barrier, podocytes stabilize the glomerular architecture by counteracting the elastic forces distending the GBM [6]. Indeed, the hydraulic pressure within glomerular capillaries is unusually high compared to other capillary beds [16]. It is estimated that podocytes are responsible for approximately 40% of the hydraulic resistance of the filtration barrier [6]. Moreover, accumulating evidence suggests that dynamic signaling between the SD and focal adhesions may promote both podocyte adherence to the GBM and maintenance of glomerular filtration barrier function [7,17,18]. In support of this hypothesis, lamellipodia formation at focal adhesions are necessary for cell migration and are induced downstream of nephrin phosphorylation in cultured podocytes [19,20]; conversely, β1 integrin activation induces tyrosine phosphorylation of nephrin [21].
Load more

Recommended publications
  • TRPC5 Regulates Axonal Outgrowth in Developing Retinal Ganglion Cells
    Laboratory Investigation (2020) 100:297–310 https://doi.org/10.1038/s41374-019-0347-1 ARTICLE TRPC5 regulates axonal outgrowth in developing retinal ganglion cells 1 1 2 1 1 Mai Oda ● Hanako Yamamoto ● Hidetaka Matsumoto ● Yasuki Ishizaki ● Koji Shibasaki Received: 22 July 2019 / Revised: 15 November 2019 / Accepted: 15 November 2019 / Published online: 16 December 2019 © The Author(s), under exclusive licence to United States and Canadian Academy of Pathology 2019 Abstract The TRPC5 ion channel is activated upon depletion of intracellular calcium stores, as well as by various stimuli such as nitric oxide (NO), membrane stretch, and cold temperatures. TRPC5 is abundantly expressed in the central nervous system where it has important neuronal functions. In the chick retina, TRPC5 expression was shown to be restricted to amacrine cells (ACs) and Müller glial cells, although its expression was also observed in the ganglion cell layer (GCL) in displaced ACs, as determined by their characteristic cell morphology. However, it is possible that this expression analysis alone might be insufficient to fully understand the expression of TRPC5 in retinal ganglion cells (RGCs). Hence, we analyzed TRPC5 expression by in situ hybridization and immunostaining in the developing mouse retina, and for the first time identified that 1234567890();,: 1234567890();,: developing and mature RGCs strongly express TRPC5. The expression begins at E14.5, and is restricted to ACs and RGCs. It was reported that TRPC5 negatively regulates axonal outgrowth in hippocampal neurons. We thus hypothesized that TRPC5 might have similar functions in RGCs since they extend very long axons toward the brain, and this characteristic significantly differs from other retinal cell types.
    [Show full text]
  • TRPC1 Regulates the Activity of a Voltage-Dependent Nonselective Cation Current in Hippocampal CA1 Neurons
    cells Article TRPC1 Regulates the Activity of a Voltage-Dependent Nonselective Cation Current in Hippocampal CA1 Neurons 1, 1 1,2 1,3, Frauke Kepura y, Eva Braun , Alexander Dietrich and Tim D. Plant * 1 Pharmakologisches Institut, BPC-Marburg, Fachbereich Medizin, Philipps-Universität Marburg, Karl-von-Frisch-Straße 2, 35043 Marburg, Germany; [email protected] (F.K.); braune@staff.uni-marburg.de (E.B.); [email protected] (A.D.) 2 Walther-Straub-Institut für Pharmakologie und Toxikologie, Ludwig-Maximilians-Universität München, 80336 München, Germany 3 Center for Mind, Brain and Behavior, Philipps-Universität Marburg, 35032 Marburg, Germany * Correspondence: plant@staff.uni-marburg.de; Tel.: +49-6421-28-65038 Present address: Institut für Bodenkunde und Pflanzenernährung/Institut für angewandte Ökologie, y Hochschule Geisenheim University, Von-Lade-Str. 1, 65366 Geisenheim, Germany. Received: 27 November 2019; Accepted: 14 February 2020; Published: 18 February 2020 Abstract: The cation channel subunit TRPC1 is strongly expressed in central neurons including neurons in the CA1 region of the hippocampus where it forms complexes with TRPC4 and TRPC5. To investigate the functional role of TRPC1 in these neurons and in channel function, we compared current responses to group I metabotropic glutamate receptor (mGluR I) activation and looked +/+ / for major differences in dendritic morphology in neurons from TRPC1 and TRPC1− − mice. mGluR I stimulation resulted in the activation of a voltage-dependent nonselective cation current in both genotypes. Deletion of TRPC1 resulted in a modification of the shape of the current-voltage relationship, leading to an inward current increase. In current clamp recordings, the percentage of neurons that responded to depolarization in the presence of an mGluR I agonist with a plateau / potential was increased in TRPC1− − mice.
    [Show full text]
  • TRP CHANNELS AS THERAPEUTIC TARGETS TRP CHANNELS AS THERAPEUTIC TARGETS from Basic Science to Clinical Use
    TRP CHANNELS AS THERAPEUTIC TARGETS TRP CHANNELS AS THERAPEUTIC TARGETS From Basic Science to Clinical Use Edited by ARPAD SZALLASI MD, PHD Department of Pathology, Monmouth Medical Center, Long Branch, NJ, USA AMSTERDAM • BOSTON • HEIDELBERG • LONDON NEW YORK • OXFORD • PARIS • SAN DIEGO SAN FRANCISCO • SINGAPORE • SYDNEY • TOKYO Academic Press is an imprint of Elsevier Academic Press is an imprint of Elsevier 125 London Wall, London, EC2Y 5AS, UK 525 B Street, Suite 1800, San Diego, CA 92101-4495, USA 225 Wyman Street, Waltham, MA 02451, USA The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, UK First published 2015 Copyright © 2015 Elsevier Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangement with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein). Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein.
    [Show full text]
  • Snapshot: Mammalian TRP Channels David E
    SnapShot: Mammalian TRP Channels David E. Clapham HHMI, Children’s Hospital, Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA TRP Activators Inhibitors Putative Interacting Proteins Proposed Functions Activation potentiated by PLC pathways Gd, La TRPC4, TRPC5, calmodulin, TRPC3, Homodimer is a purported stretch-sensitive ion channel; form C1 TRPP1, IP3Rs, caveolin-1, PMCA heteromeric ion channels with TRPC4 or TRPC5 in neurons -/- Pheromone receptor mechanism? Calmodulin, IP3R3, Enkurin, TRPC6 TRPC2 mice respond abnormally to urine-based olfactory C2 cues; pheromone sensing 2+ Diacylglycerol, [Ca ]I, activation potentiated BTP2, flufenamate, Gd, La TRPC1, calmodulin, PLCβ, PLCγ, IP3R, Potential role in vasoregulation and airway regulation C3 by PLC pathways RyR, SERCA, caveolin-1, αSNAP, NCX1 La (100 µM), calmidazolium, activation [Ca2+] , 2-APB, niflumic acid, TRPC1, TRPC5, calmodulin, PLCβ, TRPC4-/- mice have abnormalities in endothelial-based vessel C4 i potentiated by PLC pathways DIDS, La (mM) NHERF1, IP3R permeability La (100 µM), activation potentiated by PLC 2-APB, flufenamate, La (mM) TRPC1, TRPC4, calmodulin, PLCβ, No phenotype yet reported in TRPC5-/- mice; potentially C5 pathways, nitric oxide NHERF1/2, ZO-1, IP3R regulates growth cones and neurite extension 2+ Diacylglycerol, [Ca ]I, 20-HETE, activation 2-APB, amiloride, Cd, La, Gd Calmodulin, TRPC3, TRPC7, FKBP12 Missense mutation in human focal segmental glomerulo- C6 potentiated by PLC pathways sclerosis (FSGS); abnormal vasoregulation in TRPC6-/-
    [Show full text]
  • Involvement of TRPC4 and 5 Channels in Persistent Firing in Hippocampal CA1 Pyramidal Cells
    cells Article Involvement of TRPC4 and 5 Channels in Persistent Firing in Hippocampal CA1 Pyramidal Cells Alberto Arboit 1,2,3, Antonio Reboreda 1,4 and Motoharu Yoshida 1,3,4,5,* 1 German Center for Neurodegenerative Diseases (DZNE), 39120 Magdeburg, Germany; [email protected] (A.A.); [email protected] (A.R.) 2 Otto-von-Guericke University, 39120 Magdeburg, Germany 3 Faculty of Psychology, Ruhr University Bochum (RUB), Universitätsstraße 150, 44801 Bochum, Germany 4 Leibniz Institute for Neurobiology (LIN), 39118 Magdeburg, Germany 5 Center for Behavioral Brain Sciences (CBBS), 39106 Magdeburg, Germany * Correspondence: [email protected] Received: 1 December 2019; Accepted: 1 February 2020; Published: 5 February 2020 Abstract: Persistent neural activity has been observed in vivo during working memory tasks, and supports short-term (up to tens of seconds) retention of information. While synaptic and intrinsic cellular mechanisms of persistent firing have been proposed, underlying cellular mechanisms are not yet fully understood. In vitro experiments have shown that individual neurons in the hippocampus and other working memory related areas support persistent firing through intrinsic cellular mechanisms that involve the transient receptor potential canonical (TRPC) channels. Recent behavioral studies demonstrating the involvement of TRPC channels on working memory make the hypothesis that TRPC driven persistent firing supports working memory a very attractive one. However, this view has been challenged by recent findings that persistent firing in vitro is unchanged in TRPC knock out (KO) mice. To assess the involvement of TRPC channels further, we tested novel and highly specific TRPC channel blockers in cholinergically induced persistent firing in mice CA1 pyramidal cells for the first time.
    [Show full text]
  • Heteromeric TRP Channels in Lung Inflammation
    cells Review Heteromeric TRP Channels in Lung Inflammation Meryam Zergane 1, Wolfgang M. Kuebler 1,2,3,4,5,* and Laura Michalick 1,2 1 Institute of Physiology, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany; [email protected] (M.Z.); [email protected] (L.M.) 2 German Centre for Cardiovascular Research (DZHK), 10785 Berlin, Germany 3 German Center for Lung Research (DZL), 35392 Gießen, Germany 4 The Keenan Research Centre for Biomedical Science, St. Michael’s Hospital, Toronto, ON M5B 1W8, Canada 5 Department of Surgery and Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada * Correspondence: [email protected] Abstract: Activation of Transient Receptor Potential (TRP) channels can disrupt endothelial bar- rier function, as their mediated Ca2+ influx activates the CaM (calmodulin)/MLCK (myosin light chain kinase)-signaling pathway, and thereby rearranges the cytoskeleton, increases endothelial permeability and thus can facilitate activation of inflammatory cells and formation of pulmonary edema. Interestingly, TRP channel subunits can build heterotetramers, whereas heteromeric TRPC1/4, TRPC3/6 and TRPV1/4 are expressed in the lung endothelium and could be targeted as a protec- tive strategy to reduce endothelial permeability in pulmonary inflammation. An update on TRP heteromers and their role in lung inflammation will be provided with this review. Keywords: heteromeric TRP assemblies; pulmonary inflammation; endothelial permeability; TRPC3/6; TRPV1/4; TRPC1/4 Citation: Zergane, M.; Kuebler, W.M.; Michalick, L. Heteromeric TRP Channels in Lung Inflammation. Cells 1. Introduction 2021, 10, 1654. https://doi.org Pulmonary microvascular endothelial cells are a key constituent of the blood air bar- /10.3390/cells10071654 rier that has to be extremely thin (<1 µm) to allow for rapid and efficient alveolo-capillary gas exchange.
    [Show full text]
  • FKBP52 Regulates TRPC3-Dependent Ca<Sup>
    © 2019. Published by The Company of Biologists Ltd | Journal of Cell Science (2019) 132, jcs231506. doi:10.1242/jcs.231506 RESEARCH ARTICLE FKBP52 regulates TRPC3-dependent Ca2+ signals and the hypertrophic growth of cardiomyocyte cultures Sandra Bandleon1, Patrick P. Strunz1, Simone Pickel2, Oleksandra Tiapko3, Antonella Cellini1, Erick Miranda-Laferte2 and Petra Eder-Negrin1,* ABSTRACT A single TRPC subunit is composed of six transmembrane The transient receptor potential (TRP; C-classical, TRPC) channel domains with a pore-forming loop connecting the transmembrane ‘ ’ TRPC3 allows a cation (Na+/Ca2+) influx that is favored by the domains 5 and 6, a preserved 25 amino acid sequence called a TRP domain and two cytosolic domains, an N-terminal ankyrin repeat stimulation of Gq protein-coupled receptors (GPCRs). An enhanced TRPC3 activity is related to adverse effects, including pathological domain and a C-terminal coiled-coil domain (Eder et al., 2007; Fan hypertrophy in chronic cardiac disease states. In the present study, et al., 2018). The cytosolic domains mediate ion channel formation we identified FK506-binding protein 52 (FKBP52, also known as and are implicated in ion channel regulation and plasma membrane FKBP4) as a novel interaction partner of TRPC3 in the heart. FKBP52 targeting (Eder et al., 2007). Among several protein interaction sites, was recovered from a cardiac cDNA library by a C-terminal TRPC3 the C-terminus of all TRPC subunits harbors a highly conserved fragment (amino acids 742–848) in a yeast two-hybrid screen. proline-rich sequence that corresponds to the binding domain in the Drosophila Downregulation of FKBP52 promoted a TRPC3-dependent photoreceptor channel TRPL for the FK506-binding hypertrophic response in neonatal rat cardiomyocytes (NRCs).
    [Show full text]
  • TRPC5 Does Not Cause Or Aggravate Glomerular Disease
    BRIEF COMMUNICATION www.jasn.org TRPC5 Does Not Cause or Aggravate Glomerular Disease Xuexiang Wang , Ranadheer R. Dande, Hao Yu, Beata Samelko, Rachel E. Miller, Mehmet M. Altintas, and Jochen Reiser Department of Medicine, Rush University Medical Center, Chicago, Illinois ABSTRACT Transient receptor potential channel 5 (TRPC5) is highly expressed in brain and or pharmacologic inhibition of TRPC5 pro- kidney and mediates calcium influx and promotes cell migration. In the kidney, loss tected mice from albuminuria. Yet, the di- of TRPC5 function has been reported to benefit kidney filter dynamics by balancing rect effect of TRPC5 overexpression in mice podocyte cytoskeletal remodeling. However, in vivo gain-in-function studies of was not shown and a direct pathogenic TRPC5 with respect to kidney function have not been reported. To address this role of TRPC5 for proteinuria remained gap, we developed two transgenic mouse models on the C57BL/6 background by obscure. overexpressing either wild-type TRPC5 or a TRPC5 ion-pore mutant. Compared with We generated two novel transgenic nontransgenic controls, neither transgenic model exhibited an increase in protein- mouse models by overexpression of ei- uria at 8 months of age or a difference in LPS-induced albuminuria. Moreover, acti- ther wild-type TRPC5 (TG) or pore mu- vation of TRPC5 by Englerin A did not stimulate proteinuria, and inhibition of TRPC5 tant dominant negative TRPC5 (DN) in by ML204 did not significantly lower the level of LPS-induced proteinuria in any mice on a C57BL/6 background (B/6). group. Collectively, these data suggest that the overexpression or activation of With these unique models, we have the the TRPC5 ion channel does not cause kidney barrier injury or aggravate such injury opportunity to investigate the functional under pathologic conditions.
    [Show full text]
  • Trpc6) Channel in Metastasis of Glioblastoma Multiforme
    University of Central Florida STARS Electronic Theses and Dissertations, 2004-2019 2008 Role Of Transient Receptor Potential Canonical-6 (trpc6) Channel In Metastasis Of Glioblastoma Multiforme Rajarajeshwari Venkataraman University of Central Florida Part of the Cancer Biology Commons, Microbiology Commons, Molecular Biology Commons, and the Oncology Commons Find similar works at: https://stars.library.ucf.edu/etd University of Central Florida Libraries http://library.ucf.edu This Masters Thesis (Open Access) is brought to you for free and open access by STARS. It has been accepted for inclusion in Electronic Theses and Dissertations, 2004-2019 by an authorized administrator of STARS. For more information, please contact [email protected]. STARS Citation Venkataraman, Rajarajeshwari, "Role Of Transient Receptor Potential Canonical-6 (trpc6) Channel In Metastasis Of Glioblastoma Multiforme" (2008). Electronic Theses and Dissertations, 2004-2019. 3714. https://stars.library.ucf.edu/etd/3714 ROLE OF TRANSIENT RECEPTOR POTENTIAL CANONICAL-6 (TrpC6) CHANNEL IN METASTASIS OF GLIOBLASTOMA MULTIFORME By RAJARAJESHWARI VENKATARAMAN B.Sc. Mysore University, India, 1996 M.Sc. Maniple Academy of Higher Education, India, 1999 A thesis submitted in partial fulfillment of the requirements For the degree of Master of Science In the Department of Molecular Biology and Microbiology In the Brunet School of Biomedical sciences In the College of Medicine At the University of Central Florida Orlando, Florida Fall Term 2008 ABSTRACT Glioblastoma multiforme (GBM) is one of the extremely fatal brain tumors. The main reason that makes it so lethal is its capability to invade and spread to other parts of CNS producing secondary tumors. Among other factors hypoxia, reduced oxygen availability, is linked to higher metastatic potential of cancers.
    [Show full text]
  • Transient Receptor Potential Cation Channel, Subfamily C, Member 5 (TRPC5) Is a Cold-Transducer in the Peripheral Nervous System
    Transient receptor potential cation channel, subfamily C, member 5 (TRPC5) is a cold-transducer in the peripheral nervous system Katharina Zimmermanna,b,1,2, Jochen K. Lennerza,c,d,1,3, Alexander Heina,1,4, Andrea S. Linke, J. Stefan Kaczmareka,b, Markus Dellinga, Serdar Uysala, John D. Pfeiferc, Antonio Riccioa, and David E. Claphama,b,f,5 Departments of aCardiology, Manton Center for Orphan Disease, and bNeurobiology, Harvard Medical School, Boston, MA 02115; cDepartment of Pathology and Immunology, Washington University, St. Louis, MO, 63110; dDepartment of Pathology, Massachusetts General Hospital/Harvard Medical School, Boston, MA, 02116; eDepartment of Physiology and Pathophysiology, University Erlangen, 91054 Erlangen, Germany; and fHoward Hughes Medical Institute, Harvard Medical School, Children’s Hospital Boston, Boston, MA 02115 Contributed by David E. Clapham, September 20, 2011 (sent for review August 9, 2011) Detection and adaptation to cold temperature is crucial to survival. affected perforce by temperature, even if driven solely by con- Cold sensing in the innocuous range of cold (>10–15 °C) in the ventional NaV and KV channels—but high Q10 channels are likely mammalian peripheral nervous system is thought to rely primarily suspects in encoding temperature changes. Although TRPM8 on transient receptor potential (TRP) ion channels, most notably (a menthol receptor) is generally considered the primary cold – the menthol receptor, TRPM8. Here we report that TRP cation sensor for innocuous cold (11 13), and TRPA1 participates in channel, subfamily C member 5 (TRPC5), but not TRPC1/TRPC5 het- noxious cold sensing (9, 10) (14), many cold-sensitive neurons eromeric channels, are highly cold sensitive in the temperature lack TRPM8 as well as TRPA1 (15).
    [Show full text]
  • Transient Receptor Potential Canonical (TRPC) Channels As Modulators of Migration and Invasion
    International Journal of Molecular Sciences Review Transient Receptor Potential Canonical (TRPC) Channels as Modulators of Migration and Invasion Muhammad Yasir Asghar 1,2 and Kid Törnquist 1,2,* 1 Minerva Foundation Institute for Medical Research, Biomedicum Helsinki 2U, Tukholmankatu 8, 00290 Helsinki, Finland; yasir.asghar@helsinki.fi 2 Faculty of Science and Engineering, Cell Biology, Åbo Akademi University, Tykistökatu 6A, 20520 Turku, Finland * Correspondence: ktornqvi@abo.fi Received: 11 February 2020; Accepted: 26 February 2020; Published: 3 March 2020 Abstract: Calcium (Ca2+) is perhaps the most versatile signaling molecule in cells. Ca2+ regulates a large number of key events in cells, ranging from gene transcription, motility, and contraction, to energy production and channel gating. To accomplish all these different functions, a multitude of channels, pumps, and transporters are necessary. A group of channels participating in these processes is the transient receptor potential (TRP) family of cation channels. These channels are divided into 29 subfamilies, and are differentially expressed in man, rodents, worms, and flies. One of these subfamilies is the transient receptor potential canonical (TRPC) family of channels. This ion channel family comprises of seven isoforms, labeled TRPC1–7. In man, six functional forms are expressed (TRPC1, TRPC3–7), whereas TRPC2 is a pseudogene; thus, not functionally expressed. In this review, we will describe the importance of the TRPC channels and their interacting molecular partners in the etiology of cancer, particularly in regard to regulating migration and invasion. Keywords: TRPC; ion channels; cancer; thyroid; calcium; migration; invasion; angiogenesis 1. Introduction Increasing evidence during the past decade indicates that different ion channels are expressed in several cancers in humans, and regulate a multitude of cellular processes, including migration, invasion and proliferation [1–3].
    [Show full text]
  • 1 Structural Basis of TRPC4 Regulation by Calmodulin And
    bioRxiv preprint doi: https://doi.org/10.1101/2020.06.30.180778; this version posted July 1, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 1 Structural basis of TRPC4 regulation by calmodulin and pharmacological agents 2 3 Deivanayagabarathy Vinayagam1, Dennis Quentin1, Oleg Sitsel1, Felipe Merino1,2, Markus 4 Stabrin1, Oliver Hofnagel1, Maolin Yu3, Mark W. Ledeboer3, Goran Malojcic3, Stefan 5 Raunser1 6 7 1Department of Structural Biochemistry, Max Planck Institute of Molecular Physiology, 44227 8 Dortmund, Germany 9 2Current address: Department of Protein Evolution, Max Planck Institute for Developmental 10 Biology, 72076 Tübingen, Germany 11 3Goldfinch Bio, 215 First St, Cambridge, MA 02142, USA 12 Correspondence: [email protected] 13 14 15 ABSTRACT 16 Canonical transient receptor potential channels (TRPC) are involved in receptor-operated 17 and/or store-operated Ca2+ signaling. Inhibition of TRPCs by small molecules was shown to be 18 promising in treating renal diseases. In cells, the channels are regulated by calmodulin. 19 Molecular details of both calmodulin and drug binding have remained elusive so far. Here we 20 report structures of TRPC4 in complex with a pyridazinone-based inhibitor and a pyridazinone- 21 based activator and calmodulin. The structures reveal that both activator and inhibitor bind to 22 the same cavity of the voltage-sensing-like domain and allow us to describe how structural 23 changes from the ligand binding site can be transmitted to the central ion-conducting pore of 24 TRPC4.
    [Show full text]